Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
One method of providing a pharmaceutical compound in a solid form is to precipitate the compound from a solution by combining an anti-solvent and a solution of a compound to be precipitated (solvent/anti-solvent precipitation processes). Generally, when preparing a precipitate using solvent/anti-solvent precipitation processes, the characteristics of the precipitated material show increasing sensitivity to the presence of concentration gradients created during solution and anti-solvent mixing with increasing rapidity of particle formation upon combining the solution and anti-solvent. Examples of the precipitated product characteristics which can be affected by the presence of concentration gradients in a solvent/anti-solvent precipitation process include the range of primary particle sizes provided by the precipitation process, the size, bulk surface area, and bulk density of precipitated particles (agglomerates of primary particles), and the amount of solvent included in the precipitated particles.
Solvent/anti-solvent precipitation processes are typically carried out in a batch process. In general, batch processes are run by introducing, at a slow rate under mixing conditions, small aliquots of a solution of the compound to be precipitated into a tank containing the anti-solvent. It is common in batch processes of this type for the mixing shear in the anti-solvent tank to be insufficient to provide mixing of the anti-solvent and the solution that is sufficiently free from concentration gradients that the process provides particles of consistent and controlled size range with low solvent inclusion.
Solvent/anti-solvent precipitation processes in which nucleation rate is on the same order of magnitude as, or faster than, the rate of mixing are said to be mixing-controlled processes. In mixing-controlled processes for producing precipitated particle materials some workers have adopted methods which include high-velocity impinging of substantially opposed streams of solvent and anti-solvent to provide better control of particle size range and maintain low solvent inclusion in the precipitated material, see for example U.S. Pat. No. 5,314,506 to Midler et al. (the '506 patent), and U.S. Pat. No. 6,558,435 to Am-Ende et al., each of which teaches producing crystals of controlled size by utilizing substantially diametrically opposed impinging jets of solution and anti-solvent to produce high-intensity micromixing and precipitate crystals of the dissolved compound. U.S. Pat. No. 6,302,958 to Lindrud et al., teaches utilizing the impinging streams as taught in the '506 patent and in addition utilizing an ultrasonic probe placed in the zone of impingement to increase the mixing rate to a point at which the rate of homogenization of the admixed liquids is on a time scale smaller than the crystal nucleation time within the mixing zone. Each of these solutions to mixing controlled precipitation requires the use of precise mechanisms and relies on precise control of fluid dynamics to control the physical aspects of the crystalline solids precipitated.
U.S. Pat. No. 7,012,066 to Saskena, et al. (the '066 patent) describes 6,6-dimethyl-3-aza-bicyclo[3.1.0]-hexane-amide compounds of Formula A,
    wherein Ra represents the moieties described in the '066 patent as R3, Z, R4, W and Y, and Rb represents the moieties described in the '066 patent as methylene substituted by R1 and R2. One specific example of the compounds described in the '066 patent is 3-[2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide (the compound of Formula B, see the '066 patent at col. 113, Example XXIV (cols. 448 to 451) and col. 1259). These compounds have desirable properties as hepatitis C virus (HCV) protease inhibitors in the treatment of HCV infections.

When incorporating such compounds into a medicament for the treatment or prevention of conditions amenable to HCV protease inhibitor therapy, it is desirable to provide an active compound used in a pharmaceutical formulation (API), for example, a compound of Formulae A or B, in a highly pure form which has consistent physical properties, for example, in the form of an agglomerated particulate material having an average size in the micron range, with a narrow particulate size distribution, consistent bulk density, low amounts of included solvent, and a sharply defined melting point. It is preferable if a compound can be crystallized as the dynamics of crystallization can be employed to insure high purity and utilized to insure uniform physical properties. Attempts to provide the compound of Formula B in a crystalline form have not met with success.
In the provision of compounds suitable for pharmaceutical use it is common practice to purify and isolate pharmaceutically active compounds by precipitating the solid compound from a solution of the compound. One common precipitation method, termed herein “the solution/anti-solvent method”, is carried out by mixing a solution of the desired compound into a sufficient amount of an anti-solvent to provide a solvent/anti-solvent mixture in which the desired compound has reduced solubility. Accordingly, upon mixing a solution of the desired compound and an anti-solvent, the desired compound forms primary particles which aggregate and precipitate from the combined liquids forming a slurry comprising precipitated particles and the combined solvent and anti-solvent liquid.
When the solvent/anti-solvent method is applied to the provision of the compound of Formula B in a batch crystallizer, there is precipitated an amorphous, particulate material which has highly varied primary particle size and a wide range in size of agglomerates, necessitating secondary classification of the particulate material produced from the precipitation process. Moreover, the precipitation product of the compound of Formula B provided from a batch crystallizer by the solution/anti-solvent method yields a precipitated material which retains a widely varied amount of solvent, batch to batch, and often provides a product which either requires a prolonged drying time to drive off the excess included solvent or has the form of a gum rather than a particle form, and accordingly is unusable.